Hepatic fibrosis, the accumulation of abnormal extracellular matrix (ECM) proteins and a resultant loss of liver function, is an accompaniment of an inflammation-driven wound healing process triggered by chronic liver injury. Some of the main causes of liver injury leading to fibrosis include chronic hepatitis C virus (HCV) infection, alcohol abuse, chronic hepatitis B (HBV) infection, iron overload as occurs in hereditary hemochromatosis, drug induced liver injury (DILI), and increasingly non-alcoholic steatohepatitis (NASH) and non-alcoholic fatty liver disease (NAFLD).
Fibrosis of the liver is characterized by excessive deposition of ECM components, predominately type I collagen. Cytokine signaling predominates during fibrogenesis, serving to initiate activation of resident immune and hepatic stellate cells (HSCs) promoting wound repair. Activated HSCs are the principal cell type promoting synthesis and deposition of ECM proteins in response to increased levels of circulating inflammatory signals derived from damaged parenchymal cells. These resident vitamin A storing cells are found within the perisinusoidal space of Disse in a quiescent state, but upon hepatic injury the HSCs transdifferentiate into myofibroblast-like cells marked by expression of smooth muscle α-actin (αSMA), loss of retinyl ester stores, and increased proliferation and contractility. Myofibroblastic HSCs respond to and secrete a variety of profibrogenic cytokines including connective tissue growth factor (CTGF), tissue inhibitor of metalloproteinases, and transforming growth factor-beta (TGFβ). Of these, TGFβ has been recognized as the most potent fibrogenic cytokine regulating collagen production in HSCs via autocrine and paracrine signaling pathways.
The inflammatory process ensuing from hepatic injury triggers a variety of cellular responses including cell repair, hepatocyte regeneration, increased ECM turnover, and ultimately in some patients significant fibrosis. Disproportionate deposition of fibrillar collagens disrupts normal liver architecture and hepatic function and, if left untreated, may progress to cirrhosis and hepatocelluar carcinoma. Cirrhosis is a significant cause of morbidity and mortality worldwide. Accordingly there is an urgent need for antifibrotic therapies designed to impede and/or reverse fibrogenesis. See, e.g., Friedman (2010), Nat. Rev. Gastroenterol. Hepatol. 7:425-436.